The feline major histocompatibility complex (MHC) has been studied for an approach to comparative gene organization of this multigene cluster in mammals. In a large scale sequencing project of the feline MHC, we have constructed sequence contigs consisting of 1,170,994 base pairs (bps) in feline MHC class I and class II regions.A complete nucleotide sequence consisting of 632,604 bp which comprises 539,262 bp of the classical class II region spanning from DPB to butyrophilin II (BTL II) genes , plus 93,342 bp in the extended class II region, was determined for the major histocompatibility complex of the domestic cat. The domestic cat MHC class II region maintained the framework of the human MHC extended class II region, having ARE1, KE4, KE6, RING1, RXRB, COL11A2 genes and also the framework of a half of the human MHC classical class II region, containing DOA, RING3, DMA, DMB, LMP2, TAP1, LMP7, TAP2, DOB genes. However, all DP, DQ and DR subregions of the domestic cat MHC were drastically changed. Only one pair of human DPA and DPB gene homologues were found in the cat DP subregion with the similar deleterious mutations in the coding region of cat DPA genes found in human DPA2 pseudogene. The entire DQ subregion was deleted. The DR subregion includes four DRB genes (DRB1, pseudoDRB2, DRB3, DRB4) and three DRA genes (DRA1, DRA2, DRA3), presumably generated by two duplication events of appx. 30 kb DNA fragments and a single inversion event. Three pseudogenes, vacuolar ATPase, glyceraldehyde 3-phosphate dehydrogenese (GAPDH) and SURF-3 (L7a ribosomal protein) genes were translocated in the cat MHC class II region. The domestic cat MHC class II region maintained the same profile with a low GC content (42.7 %) as human classical class II region (42.3 %), which is a characteristics of isochore. Approximately 37 % (233,996 bp) of the sequence were consisted of mammalian repeat elements, including 330 SINEs, 56 MIRs, 187 LINEs, 33 LTR elements , 45 MER elements and 184 simple repeats and 106 low complexity repeats.